Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation
Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation
复制标题
DOI：
10.1073/pnas.0712366105
复制
发表时间：
2008-03-11
影响因子：
11.1
通讯作者：
Giordano, Frank J.
中科院分区：
文献类型：
--
作者：
Hao, Zhengrong;Huang, Yan;Giordano, Frank J.
促肾上腺皮质激素释放因子 (CRF) 受体 CRFR2 在外周组织和脉管系统中广泛表达，尽管其在这些组织中的功能作用最近才开始被阐明。此前我们发现 CRFR2 基因缺失导致小鼠产后严重血管化，其特征是血管总数增加和血管直径急剧增加。这些数据强烈表明 CRFR2 的配体可以限制组织血管分布，也许是作为促进新血管形成的因素的平衡。尿皮质素 2 (Ucn2) 是 CRFR2 的特异性配体。我们假设 Ucn2 激活 CRFR2 可能会抑制肿瘤血管形成，从而限制肿瘤生长。在这里，我们发现病毒介导的 Ucn2 表达显着抑制体内 Lewis 肺癌细胞 (LLCC) 肿瘤的生长和血管化。此外，我们发现这种对肿瘤生长抑制的作用与暴露于Ucn2是发生在可测量肿瘤建立之前还是之后无关。在体外，Ucn2直接抑制LLCC的增殖，表明CRFR2激活的抑癌作用涉及直接抑制肿瘤细胞周期和抑制肿瘤血管化的双重机制。这些结果证实 Ucn2 抑制肿瘤生长，表明 CRFR2 配体在临床恶性肿瘤中具有潜在的治疗作用。
The corticotropin-releasing factor (CRF) receptor CRFR2 is expressed widely in peripheral tissues and in the vasculature, although its functional roles in those tissues have only recently begun to be elucidated. Previously we found that genetic deletion of CRFR2 resulted in profound postnatal hypervascularization in mice, characterized by both an increase in total vessel number and a dramatic increase in vessel diameter. These data strongly suggested that ligands for CRFR2 act to limit tissue vascularity, perhaps as a counterbalance to factors that promote neovascularization. Urocortin 2 (Ucn2) is a specific ligand for the CRFR2. We hypothesized that activation of CRFR2 by Ucn2 might thus suppress tumor vascularization and consequently limit tumor growth. Here, we show that viral-mediated expression of Ucn2 strikingly inhibits the growth and vascularization of Lewis Lung Carcinoma Cell (LLCC) tumors in vivo. Further, we found that this effect on tumor growth inhibition was independent of whether exposure to Ucn2 occurred before or after establishment of measurable tumors. In vitro, Ucn2 directly inhibited the proliferation of LLCC, suggesting that the tumor-suppressing effects of CRFR2 activation involve a dual mechanism of both a direct inhibition of tumor cell cycling and the suppression of tumor vascularization. These results establish that Ucn2 inhibits tumor growth, suggesting a potential therapeutic role for CRFR2 ligands in clinical malignancies.